PROJECT SUMMARY/ABSTRACT The long-term goal of this grant project is to understand the immunological mechanisms of asthma. Airway inflammation in patients with asthma is generally characterized by increased numbers of eosinophils and lymphocytes producing Th2 cytokines. However, the mechanisms involved in development of Th2-type CD4+ T cells and persistent and/or recurrent production of Th2 cytokines in the airways are not fully understood. Recently, we and other investigators have identified in mouse lungs novel type 2 innate lymphoid cells (ILC2s) that are responsive to IL-33. Airway exposure to aeroallergens induces IL-33 production in the lungs, and administration of exogenous IL-33 promotes development of antigen-specific Th2-type CD4+ T cells. Furthermore, ILC2s and conventional CD4+ T cells work together synergistically, resulting in production of large quantities of Th2 cytokines in vitro. Therefore, we hypothesize that ILC2s are involved in the development of robust Th2-type immune responses and persistent inflammation in respiratory tract exposed to airborne allergens, leading to chronic airway diseases such as asthma. In Aim 1, we will determine the roles of ILC2s in development of antigen-specific Th2-type CD4+ T cells. By using in vitro experiments and IL-33-driven mouse airway sensitization models, we will investigate how ILC2s are involved in the development and/or maintenance of antigen-specific Th2-type CD4+ T cells in the lungs. In Aim 2, we will determine the roles of ILC2s and conventional Th2-type CD4+ T cells in asthma. By using a mouse model of chronic asthma (i.e. mice exposed repeatedly to environmental allergens), we will dissect the roles for synergistic interactions between ILC2s and CD4+ T cells in persistent airway inflammation and lung pathology. In Aim 3, we will investigate the roles of ILC2s in human asthma. We will collect peripheral blood specimens from allergic asthma patients and from control individuals and examine whether IL-33-responsive ILC2s are increased and/or functionally activated in patients with asthma. We have developed several robust mouse models to dissect the Th2-type immune responses and airway inflammation to airborne allergens. All of the tools necessary to accomplish this project, including gene-deficient mice, cytokine reporter mice and adoptive cell transfer models, are currently available in our laboratory. An outstanding group of investigators, including an asthma specialist, will participate in this project. Therefore, the proposed studies are likely to provide fundamental information regarding the mechanisms by which Th2-type immune responses and airway inflammation develop and persist after exposure to environmental allergens. They will provide a new understanding of the pathogenesis of asthma and will lead to the development of novel treatments and prevention strategies for asthma and other Th2-type airway inflammatory disorders.